Maintenance of tolerance to self-antigens is essential for the prevention of autoimmunity that involves regulatory T cells (Treg), but is an incompletely understood process. CD4+CD25+ regulatory T cells have been reported to act as dominant regulators of immune activation and immune tolerance. In humans or in the murine species, one consistent feature of CD4+CD25+ regulatory T cells is the expression of the forkhead family transcription factor FOXP3. FOXP3 acts as a “sufficient” regulator of the development and function of peripheral CD4+CD25+ regulatory T cells, but the molecular mechanisms underlying FOXP3-mediated immunological regulation are still poorly understood.
“X-linked autoimmunity and allergic dysregulation syndrome” (XLAAD) or “Immunodysregulation, polyendocrinopathy and enteropathy, X-linked syndrome” (IPEX) is a fatal recessive disorder of humans that develops in early childhood. These individuals fail to develop CD4+CD25+ T cells and experience varied symptoms that include diarrhea, dermatitis, insulin-dependent diabetes, thyroiditis and anaemia. Massive T cell infiltration into the skin and gastrointestinal tract is also observed. Several XLAAD/IPEX mutations are found in the forkhead domain of FOXP3, indicating the potential disruption of DNA binding. In addition, two independent studies identified single amino acid deletions at E251 or K250 within the leucine zipper domain of FOXP3. Mutations in this region could potentially result in aberrant FOXP3 function by affecting its homo-association or association with the highly conserved leucine zipper domain of other subfamily members, such as FOXP1, FOXP2 and FOXP4.